The freshwater snail Biomphalaria glabrata plays an indispensible role in transmission of the human blood fluke, Schistosoma mansoni. Increasing our understanding of the fundamental mechanisms of internal defense of this snail could help develop novel methods of control of schistosomiasis which still infects 200 million people world-wide. Much remains unknown regarding the molecular interplay between schistosomes and their snail hosts, and the B. glabrata - S. mansoni model system is by far the best for assessing underlying mechanisms of resistance and compatibility. The proposed investigations are built on previous studies suggestive of a functional role of snail blood proteins called FREPs (fibrinogen-related proteins) in anti-schistosome defenses. They are further inspired by our discoveries showing that B. glabrata generates a surprising diversity of FREP genes through point mutation and recombination, a discovery that along with work in other labs has provoked a general reconsideration of the capacity of invertebrates to generate diversified defense responses. In this application, which has been extensively revised in response to the previous review, we develop a general approach for assessing the functionality of putative immune effectors (FREPs are the main, but not the sole, effectors available to be tested using this approach) in influencing the ability of S. mansoni to develop successfully in B. glabrata. In so doing, it is important to examine candidate effector molecules both from the perspective of their involvement in resistance to infection, and as general determinants of compatibility. Specifically, we will further develop RNA interference (RNAi) and recombinant protein/antibody approaches to examine the functional role of FREPs in affecting the development of parasites in incompatible hosts, using both in vivo and in vitro approaches. Other candidates we have recently identified, namely gram-negative bacteria binding protein (GNBP) and peptidoglycan recognition proteins (PGRPs), the snail homologs of key molecules controlling upstream Toll/Imd pathways, are also available for study, thus further broadening our understanding of snail immunity. Finally, we will attempt to disrupt the successful parasitization of compatible snails by S. mansoni. The ability to effect such disruption would be an important advance because compatibility ensures the continued transmission of schistosomiasis in endemic areas. This study will enable us to gain valuable insights into the functionality of FREPs and other candidates, and even more importantly, to develop a system of general applicability for evaluating the role of any snail candidate molecules in influencing the outcome of an encounter between S. mansoni and its snail host.